The present invention relates to an improved process for preparing substituted pyridines by oxidation (i.e., aromatization) of the corresponding 1,4-dihydropyridines.
Substituted pyridines are important products for the preparation of pharmaceutics, crop protection agents and dyes.
A large number of oxidizing agents, for example, supported iron nitrates and copper nitrates, if appropriate with the action of ultrasound, cerium ammonium nitrate, pyridinium chlorochromate, nitric acid, and nitrogen monoxide (see J. Org. Chem., 62, 3582 (1997) are known to be suitable for oxidizing (i.e., aromatizing) 1,4-dihydropyridines. Some of these oxidation methods are expensive, others require complicated apparatus and safety precautions, and others require ecologically objectionable oxidizing agents. The nitrogen monoxide recommended in the above literature reference for use as oxidizing agent must be handled under argon since it reacts with atmospheric oxygen and is expensive. According to J. Med. Chem., 29, 1596 (1986), the oxidation is carried out using nitric acid, but large amounts of nitric acid are required (12 ml of aqueous nitric acid for 0.66 g of starting material), and the product must be isolated by three extractions with ether.
To prepare 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl) pyridine, it is known to oxidize the corresponding 1,4-dihydropyridine with sulfur (see U.S. Pat. No. 4,950,675). In addition to the problematic handling of sulfur, this process has the major disadvantage that yields of only considerably less than 40% are possible and that highly toxic hydrogen sulfide is formed as by-product.
Thus, there is currently no process that is easy to carry out and cost-effective and gives high yields for preparing substituted pyridines by oxidation of the corresponding 1,4-dihydropyridines.
This invention accordingly provides a process for preparing substituted pyridines of formula (I) 
wherein
R1 and R5 are identical or different and each represents C1-C10-alkyl or C6-C10-aryl,
R2 and R4 are identical or different and each represents hydrogen, C1-C10-alkyl, CN, or COOR6 wherein R6 is C1-C10-alkyl, and
R3 represents hydrogen, C1-C10-alkyl or represents C6-C10-aryl that is optionally substituted by halogen, nitro, COOR6 (wherein R6 is C1-C10-alkyl), CN, or C1-C10-alkyl,
comprising reacting a substituted 1,4-dihydropyridine of formula (II) 
wherein R1 to R5 are as defined for formula (I),
with methyl nitrite in the presence of an acid containing less than 20% by weight of oxidizing components.
In formulas (I) and (II), R1 and R5 are preferably identical and each preferably represents straight-chain or branched C1-C6-alkyl; R2 and R4 are preferably identical, and each preferably represents COOR6 wherein R6 is straight-chain or branched C1-C6-alkyl; and R3 preferably represents fluorine- and/or chlorine-substituted phenyl.
In formulas (I) and (II), R1 and R5 particularly preferably represent isopropyl; R2 and R3 particularly preferably represent COOR6 wherein R6 is methyl or ethyl; and R3 particularly preferably represents 4-fluorophenyl.
The methyl nitrite that is required can be prepared in a simple known manner by reacting alkali metal nitrites with methanol in the presence of a strong acid. In this preparation method, the methyl nitrite is obtained in gaseous form and can be used in this form for the process according to the invention. It is advantageous to use at least the amount of methyl nitrite that is stoichiometrically required. Even relatively large excesses of methyl nitrite do not interfere with the reaction. Preference is given to using from I to 20 mol of methyl nitrite per mole of 1,4-dihydropyridine of formula (II).
A very wide variety of mineral and carboxylic acids are suitable for use as acids. Preference is given to using gaseous hydrogen chloride, aqueous hydrochloric acid, aqueous sulphuric acid and C1-C4-carboxylic acids in substance or as aqueous solution.
The amount of acid can be varied within relatively wide limits. It is possible, for example, to use catalytic, stoichiometric, or superstoichiometric amounts of acid. Preference is given to using from 0.01 to 2 mols of acid per mole of 1,4-dihydropyridine of formula (II). It is also possible to use mixtures of different acids. Carboxylic acids can also act as solvent and therefore can be set in higher molar ratios, for example up to 50 mols, preferably up to 30 mols per mol of 1,4-dihydropyridine of the formula (II).
The acid to be used contains less than 20% by weight of oxidizing components. Oxidizing components can be, for example, nitric acid or salts having oxidizing action. The content of oxidizing components in the acid is preferably below 5% by weight. Particularly preferably, the acid is free of oxidizing components.
The 1,4-dihydropyridine of formula (II) can also be employed in the form of 1,4-dihydropyridinium salts of non-oxidizing acids, for example, in the form of 1,4-dihydroxypyridine hydrochlorides. In such cases, it is possible to dispense with the separate addition of an acid.
If the acid is used in the form of an aqueous solution in such an amount that the reaction mixture forms a suspension or solution that is easy to stir, it is not necessary to add other solvents. Otherwise, it is expedient to add solvents. Suitable solvents are those that do not take part in any undesirable side reactions. Examples are water, aromatic hydro-carbons such as toluene, alcohols such as methanol, ethers such as dibutyl ether, halogenated hydrocarbons such as dichloroethane and chlorobenzene, sulfoxides such as dimethyl sulfoxide, and sulfones such as tetramethylene sulfone. Carboxylic acids can also act as solvent (see above).
If appropriate, the solvents are added in such amounts that the reaction mixture forms a suspension or solution that is easy to stir.
The process according to the invention can be carried out in different ways. For example, the 1,4-dihydropyridine of formula (II) can be suspended or dissolved in a solvent, followed by addition of the acid and introduction of gaseous methyl nitrite. It is also possible to admix the 1,4-dihydropyridine of formula (II) with such an amount of an aqueous solution of the acid that a readily stirrable suspension or solution is formed and then to introduce gaseous methyl nitrite. It is also possible to meter in the acid simultaneously but separately from the methyl nitrite.
Furthermore, it is also possible, for example, to suspend 1,4-dihydropyridine of formula (II) in water and then to introduce gaseous hydrogen chloride and then methyl nitrite. Other ways of carrying out the process according to the invention are also feasible.
Suitable reaction temperatures for the process according to the invention are, for example, between xe2x88x9230 and +100xc2x0 C., in particular from xe2x88x9210 to +65xc2x0 C.
The reaction mixture that is present after the reaction has ended can be worked up in a simple manner. If the reaction has been carried out substantially in aqueous medium, the reaction mixture can first be neutralized using any base, and the substituted pyridine of formula (I) that has been prepared can then be separated off, for example, by filtration.
If the reaction has been carried out substantially in alcoholic medium or in another water-miscible solvent, water can, after neutralization with any base, be added to the reaction mixture, and the substituted pyridine of formula (I) that has been prepared can be separated off, for example, by filtration.
If the reaction has been carried out in a water-immiscible medium, some or all of the solvent can, following neutralization with any base, be removed from the reaction mixture, thus giving the substituted pyridine of formula (I) that has been prepared.
Other simple alternatives for working up the reaction mixtures are also feasible.
The base used for neutralizing the reaction mixture can be any base that does not take part in undesirable side reactions. Suitable bases are, for example, aqueous lyes, alkoxides as such or in alcoholic solution, and amines. If the reaction is carried out in aqueous medium, preference is given to using aqueous lyes. If the reaction is carried out in an alcoholic medium, preference is given to alkoxides.
In cases where carboxylic acids are set in the neutralization can be omitted.
The process according to the invention has a number of advantages. Thus, the obtainable yields, which are generally between 90 and 99% of theory, are high, the practice is simple, the methyl nitrite can be prepared in a simple manner as required, no ecologically objectionable heavy metal salts are used for the oxidation and, as a consequence, no highly toxic by-products are formed, and work-up of the reaction mixture is simple.